Phenolic compounds naturally present in olive oil and lowering of blood LDL‐cholesterol and systolic blood pressure, therefore reducing the risk of coronary heart disease: Evaluation of a health claim pursuant to Article 14 of Regulation (EC) No 1924/2006

TL;DR

This paper evaluates if phenolic compounds in olive oil can lower LDL cholesterol and blood pressure to reduce heart disease risk.

Contribution

The paper provides a critical evaluation of the scientific evidence supporting a health claim about olive oil phenolics and heart disease risk reduction.

Findings

One study showed reduced LDL cholesterol after 3 weeks of olive oil polyphenol consumption, but results were not consistent.

No evidence was found for long-term effects or a clear mechanism for lowering LDL cholesterol.

Studies did not show a significant effect of olive oil polyphenols on systolic blood pressure.

Abstract

Following an application from QvExtra! Internacional pursuant to Article 14 of Regulation (EC) No 1924/2006 via the Competent Authority of Spain, the EFSA Panel on Nutrition, Novel Foods and Food Allergens (NDA) was asked to deliver an opinion on the scientific substantiation of a health claim related to phenolic compounds naturally present in olive oil and lowering of blood LDL‐cholesterol (LDL‐c) and systolic blood pressure (SBP), therefore reducing the risk of coronary heart disease (CHD). The scope of the application was proposed to fall under a health claim referring to disease risk reduction. The Panel considers that the food/constituent, phenolic compounds naturally present in olive oil, is sufficiently characterised, and that lowering of blood LDL‐c and SBP are beneficial effects by reducing the risk of CHD. The applicant identified seven pertinent human intervention studies investigating the effect of olive oil polyphenols on LDL‐c and/or SBP. In weighing the evidence with regard to blood LDL‐c, the Panel considered that, although one human intervention study in hypercholesteraemic individuals showed a reduction in LDL‐c following daily consumption of olive oil polyphenols for 3 weeks, these results are not supported by other studies. The Panel also considered that no evidence was available for the sustainability of the effect over longer periods of time (e.g. ≥ 8 weeks), or for a plausible mechanism of action. In weighing the evidence with regard to SBP, the Panel took into account that, although some evidence for a plausible mechanism by which phenolic compounds in olive oil could exert the claimed effect has been provided, the studies submitted did not show an effect of olive oil polyphenols on SBP. The Panel concludes that a cause‐and‐effect relationship has not been established between the consumption of phenolic compounds naturally present in olive oil and the reduction of blood LDL‐c or SBP.

Full text

INTRODUCTION

1

Background and Terms of Reference as provided by the requestor

1.1

Regulation (EC) No 1924/2006 harmonises the provisions that relate to nutrition and health claims and establishes rules governing the Community authorisation of health claims made on foods. As a rule, health claims are prohibited unless they comply with the general and specific requirements of this Regulation, are authorised in accordance with this Regulation, and are included in the lists of authorised claims provided for in Articles 13 and 14 thereof. In particular, Articles 14–17 of this Regulation lay down provisions for the authorisation and subsequent inclusion of reduction of disease risk claims and claims referring to children's development and health in a Community list of permitted claims. According to this Regulation, an application shall be submitted by the applicant to the national competent authority of a Member State, which will make the application and any supplementary information supplied by the applicant available to the European Food Safety Authority (EFSA).

Interpretation of the Terms of Reference

1.2

EFSA is requested to evaluate the scientific data submitted by the applicant in accordance with Article 16(3) of Regulation (EC) No 1924/2006. On the basis of that evaluation, EFSA will issue an opinion on the scientific substantiation of a health claim related to phenolic compounds in olive oil and lowering of blood LDL‐cholesterol and systolic blood pressure, therefore reducing the risk of coronary heart disease.

The present opinion does not constitute, and cannot be construed as, an authorisation for the marketing of phenolic compounds in olive oil, a positive assessment of their safety or a decision on whether olive oil phenolic compounds are, or are not, classified as a foodstuff. It should be noted that such an assessment is not foreseen in the framework of Regulation (EC) No 1924/2006.

It should also be highlighted that the scope, the proposed wording of the claim and the conditions of use as proposed by the applicant may be subject to changes, pending the outcome of the authorisation procedure foreseen in Article 18(4) of Regulation (EC) No 1924/2006.

DATA AND METHODOLOGIES

2

Data

2.1

Information provided by the applicant

See also section Steps taken by EFSA at the end of this opinion.

Food/constituent as stated by the applicant

According to the applicant, the constituent for which the health claim is made is ‘phenolic compounds naturally present in virgin olive oil’.

Health relationship as claimed by the applicant

Upon a request from EFSA, the applicant clarified the claimed health effect is the lowering of blood LDL‐cholesterol and systolic blood pressure, risk factors for coronary heart disease.

Mechanism by which the food/constituent could exert the claimed effect as proposed by the applicant

Regarding the mechanism by which phenolic compounds in olive oil could decrease blood LDL‐cholesterol, the applicant suggests that ‘The decrease in LDL concentrations may be explained through an improvement in the systemic oxidative status or by an increase in the gene expression of lipoprotein lipase. An improved oxidative status due to the consumption of olive oil polyphenols may counteract increases in LDL concentrations by decreasing the number of small LDL particles.’ Additionally, the applicant suggests olive oil polyphenols ‘enhance the expression of cholesterol efflux‐related genes’.

Regarding the mechanism for blood pressure reduction, the applicant suggests that ‘the polyphenols can stimulate the formation of vasoprotective factors, such as nitric oxide (NO) and endothelium‐derived hyperpolarising factor (EDHF) to promote vasodilatation, inhibit platelet aggregation in humans and they can also improve vascular smooth muscle function, by reducing the excessive vascular oxidative stress of pathological blood vessels associated with many cardiovascular risk factors.’ Additionally, the applicant proposes a reduction of blood pressure ‘through modulating the expression of genes that are related to the renin–angiotensin–aldosterone system (RAAS)’.

Wording of the health claim as proposed by the applicant

The applicant has proposed the following wording for the health claim: ‘Naturally present phenolic compounds in any virgin olive oil reduce the LDL‐cholesterol in blood and arterial systolic blood pressure. A reduction of LDL‐cholesterol in blood or arterial systolic blood pressure reduces coronary heart disease.’

Specific conditions of use as proposed by the applicant

According to the applicant, the target population for the claimed effect is ‘general healthy and subgroup with mildly raised LDL‐c and blood pressure’. The applicant recommends ‘The oil should be consumed at least in a quantity of 35 mL, to have 8 mg of phenols; and 55 mL to have 12 mg (for a significant decrease in LDL‐C and SBP respectively). To do this we must consume at least 40 mL of virgin olive oil, which would be equivalent to 4 tablespoons daily’ to achieve the claimed effect.

The applicant also states that ‘the natural phenols content in the virgin olive oil should be at least 200 mg/kg.’

Data provided by the applicant

The health claim application on phenolic compounds in olive oil pursuant to Article 14 of Regulation (EC) No 1924/2006 was presented in a common and structured format as outlined in the Scientific and technical guidance for the preparation and presentation of applications for authorisation of health claims (EFSA NDA Panel, 2021b).

As outlined in the General guidance for stakeholders on health claim applications (EFSA NDA Panel, 2021a), it is the responsibility of the applicant to provide the totality of the available evidence.

The applicant has submitted a confidential and a non‐confidential version of a dossier following the ‘General scientific guidance for stakeholders on health claim applications’ (EFSA NDA Panel, 2021a) and the ‘Scientific and technical guidance for the preparation and presentation of a health claim application’ (EFSA NDA Panel, 2021b).

The application does not contain data claimed as confidential or proprietary by the applicant.

In accordance with Art. 38 of Regulation (EC) No 178/20021 and taking into account the protection of confidential information and of personal data in accordance with Articles 39 to 39e of the same Regulation, and of the Decision of EFSA's Executive Director laying down practical arrangements concerning transparency and confidentiality,2 the non‐confidential version of the dossier has been published in the OpenEFSA portal.3

Methodologies

2.2

The general approach of the NDA Panel for the evaluation of health claim applications is outlined in the EFSA General guidance for stakeholders on health claim applications (EFSA NDA Panel, 2021a).

In assessing each specific food/health relationship, which forms the basis of a health claim, the NDA Panel considers the following key criteria:

• the food/constituent is defined and characterised;
• the claimed effect is based on the essentiality of a nutrient; OR the claimed effect is defined and is a beneficial physiological effect for the target population and can be measured in vivo in humans;
• a cause and effect relationship is established between the consumption of the food/constituent and the claimed effect (for the target group under the proposed conditions of use).

Each of these three criteria needs to be assessed by the NDA Panel with a favourable outcome for a claim to be substantiated. In addition, an unfavourable outcome of the assessment of criterion (i) and/or (ii) precludes the scientific assessment of criterion (iii).

The scientific requirements for health claims related to cardiovascular health are outlined in a specific EFSA guidance (EFSA NDA Panel, 2018).

Public consultation

2.3

According to Art. 32c(2) of Regulation (EC) No 178/2002 and to the Decision of EFSA's Executive Director laying down the practical arrangements on pre‐submission phase and public consultations, EFSA carried out a Public Consultation (PC) on the non‐confidential version of the application from 21 February 2025 to 14 March 2025 (PC‐1329) for which six comments were received. The comments received during the PC are addressed in Appendix A.

ASSESSMENT

3

Characterisation of the food/constituent

3.1

The food constituent proposed by the applicant as the subject of the health claim is ‘phenolic compounds naturally present in virgin olive oil’.

In European legislation,4 phenolic compounds are not among the parameters included in the specifications for the categorisation and grading of olive oil and olive‐pomace oil, and therefore, virgin olive oil is not characterised on the basis of its phenolic content. In the context of the scientific evidence submitted for the substantiation of the claim (Section 3.3), the Panel understands that the food constituent that is the subject of the health claim is phenolic compounds naturally present in olive oil.

The applicant specifies that the term phenolic compounds encompass both olive oil polyphenols and monophenolic compounds, such as oleocanthal.

Polyphenols are a diverse group of secondary plant metabolites, comprising several thousand compounds, including flavonoids, isoflavonoids, phenolic acids, proanthocyanidins, tannins and lignans, each with distinct biological activities. The major phenolic compounds in olive oil are simple phenols (e.g. hydroxytyrosol and tyrosol), secoiridoids (e.g. oleuropein, ligstroside and their key derivatives such as oleacein and oleocanthal) and lignans (e.g. pinoresinol). The total phenolic content in olive oil can be quantified using established analytical methods, such as the Folin–Ciocalteu spectrophotometric (colorimetric) assay (Singleton & Rossi, 1965). In the Folin–Ciocalteu assay applied to olive oil, the most commonly used standard is gallic acid, with results generally expressed as gallic acid equivalents (GAE). However, alternative standards such as caffeic acid have also been used. In a previous assessment, the Panel noted that the Folin–Ciocalteu method is not suitable for characterising polyphenols in foods in general due to its lack of specificity, as it measures all reducing compounds (e.g. sugars, ascorbic acid and proteins) and thereby can overestimate polyphenol content (EFSA NDA Panel, 2011). However, the olive oil matrix inherently lacks significant amounts of these interfering compounds, making the Folin–Ciocalteu assay an appropriate and reliable method for quantifying phenolic compounds in olive oil, as supported by Reboredo‐Rodríguez et al. (2016).

For detailed characterisation of individual phenolic compounds (e.g. hydroxytyrosol, oleuropein or ligstroside derivatives), high‐performance liquid chromatography (HPLC) coupled with UV detection is commonly employed. For enhanced sensitivity and specificity in quantifying specific phenols, particularly at low concentrations (e.g. oleocanthal, oleacein), HPLC with tandem mass spectrometry (HPLC‐MS/MS) is typically used.

The applicant suggests that phenolic compounds in olive oil should be quantified by the International Olive Council (IOC) certified method 1 (COI/T.20/Doc. No 29/Rev.12017). This method is based on the direct extraction of the minor polar phenolic compounds from olive oil by means of a methanol solution and subsequent quantification by HPLC with the aid of a UV detector at 280 nm. Following normalisation to the internal standard (syringic acid), the content of the natural and oxidised oleuropein and ligustroside derivatives, lignans, flavonoids and phenolic acids is expressed in mg/kg of tyrosol equivalents (tyrosol used as the external standard). The range of measurement is from 30 mg/kg to 800 mg/kg.

The Panel considers that the food/constituent phenolic compounds naturally present in olive oil, which is the subject of the health claim, are sufficiently characterised.

Relevance of the claimed effect to human health

3.2

The claimed effect proposed by the applicant is the lowering of blood LDL‐cholesterol and systolic blood pressure, risk factors for coronary heart disease. The proposed target population is the general healthy population, including subgroups with mildly raised LDL‐c and/or blood pressure.

As stated in the Guidance for the scientific requirements for health claims related to antioxidants, oxidative damage and cardiovascular health (EFSA NDA Panel, 2018), elevated blood LDL‐cholesterol concentration and elevated arterial systolic blood pressure (SBP) are independently associated with an increased risk of coronary heart disease (CHD) and lowering LDL‐cholesterol concentration and/or SBP would generally reduce the risk of CHD. Therefore, the scientific substantiation of claims relating to a reduced risk of CHD can be based on evidence of a reduction in either blood LDL‐cholesterol concentration or arterial SBP, and evidence of a reduction in the incidence of CHD is not required.

Regarding the study duration, blood lipids and blood pressure tend to stabilise after about 4 weeks in response to nutritional interventions. However, the time needed to reach such stabilisation may depend on the study characteristics (e.g. appropriate run‐in period) and the nature of the intervention. Evidence on the sustainability of the effect with continuous consumption of the food/constituent over longer periods of time (e.g. ≥ 8 weeks) should be provided (EFSA NDA Panel, 2018).

The Panel considers that lowering of blood LDL‐cholesterol and systolic blood pressure is a beneficial effect by reducing the risk of CHD.

Scientific substantiation of the claimed effect

3.3

The NDA Panel has previously evaluated a health claim under article 13(1) of Regulation (EC) No 1924/2006 on polyphenols in olive and the maintenance of normal blood pressure with a negative outcome. The Panel could not draw conclusions for the scientific substantiation of the claimed effect from any of the human intervention studies submitted (EFSA NDA Panel, 2011). No health claims related to phenolic compounds in olive oil and the maintenance of normal blood LDL‐c concentration or reduction of LDL‐c concentration as a risk factor for CHD have been previously assessed by EFSA.

In the current application, the applicant first aimed to identify systematic reviews registered in PROSPERO using the term ‘virgin olive oils’ and for which the results were already published in a peer‐reviewed journal. The applicant identified two published systematic reviews and meta‐analyses of human intervention studies investigating the effect of olive oil polyphenols on cardiovascular risk factors (George et al., 2019; Schwingshackl et al., 2019). The applicant assumed that these publications could encompass all human intervention studies pertinent to the claim published until December 2018. Therefore, the applicant performed a literature search in the database PubMed from January 2019 to November 2023 to identify additional studies published after that date.

The full search strategy with keywords was provided by the applicant. The eligibility criteria for inclusion were randomised controlled clinical trials (RCT) conducted in healthy and non‐healthy humans with a study duration of at least 3 weeks, reporting the effects of olive oil phenolic compounds on at least one of the following parameters: blood concentrations of total cholesterol (TC), HDL‐cholesterol (HDL‐c) or LDL‐cholesterol (LDL‐c); systolic blood pressure (SBP) or diastolic blood pressure (DBP). Only studies reporting the content of phenols in the olive oils tested and comparing with oils without phenols or with different doses were considered. Studies reporting blood lipid and/or blood pressure values at the end of the intervention only, and not changes over time, were excluded. The systematic reviews identified were scrutinised for additional relevant references that may have been omitted by the search.

A total of 11 articles, reporting on seven studies, were identified by the applicant as being pertinent to the claim. Of these, eight articles were identified via the two published systematic reviews (Al‐Rewashdeh, 2010; Covas et al., 2006; Fernández‐Castillejo et al., 2016; Gimeno et al., 2007; Hernáez et al., 2015; Marrugat et al., 2004; Perona et al., 2011; Sanchez‐Rodriguez et al., 2018) and three articles via the systematic review they conducted (Khandouzi et al., 2021; Sarapis et al., 2020; Sarapis et al., 2023).

The study by Al‐Rewashdeh (2010) is a sequential, non‐randomised intervention study where 25 adult men and women consumed olive oils containing low, medium, or high phenolic content for 4 weeks each, with a 4‐week washout period in between. All participants were instructed to consume the olive oils in the same order ad libitum in replacement of their usual fat intake. Olive oil consumption was assessed using weekly 3‐day diet recalls and food frequency questionnaires and was reported as an average intake over the study duration for the three intervention periods. Measures of LDL‐c concentration and SBP were also reported as averages for the three interventions and related washout periods. The Panel notes the sequential non‐randomised study design and that the information provided does not allow for accurate quantification of the amount of olive oil phenolic compounds consumed by participants during each intervention, nor does it allow for conclusions to be drawn about the independent effects of olive oil polyphenols on blood LDL‐c concentrations or SBP.

In the parallel, open‐label, RCT by Khandouzi et al. (2021), 50 patients with at least one cardiovascular risk factor and undergoing coronary angiography were randomly allocated to receive 25 mL/day of olive oil with either high or low polyphenol content for 6 weeks (n = 25 per group). The primary outcome of the study was plasma concentrations of IL‐6. Other inflammatory markers (both plasma concentrations and their production from whole blood culture), changes in body weight, the blood lipid profile and plasma concentrations of malondialdehyde were also assessed. A total of 40 patients (20 per group) completed the study (20% attrition rate). Reasons for withdrawal and compliance with the intervention in completers were not reported. The statistical analyses were conducted in completers only, of which 95% (19 per group) were on statins and did not account for multiplicity of outcomes. The Panel notes the significant methodological limitations of the study (i.e. participants and assessors were not blinded, high attrition rate, unknown compliance with the intervention, statistical analyses in completers only were not adjusted for multiple testing).

The study by Hernáez et al. (2015) presents the results of several LDL‐c particle‐related analyses in blood samples from a subset of volunteers (n = 25) who participated in the EUROLIVE study (n = 200), including blood LDL‐c concentrations. However, blood lipid profile parameters for the entire EUROLIVE study population, including changes in LDL‐c concentrations, are reported in another publication also submitted in this application (Covas et al., 2006). The Panel notes that, although blood LDL‐c concentrations were directly measured and not calculated as in Covas et al. (2006), this study does not provide additional information regarding the claimed effect beyond what is reported in Covas et al. (2006) for the entire EUROLIVE sample.

Similarly, as noted also by the applicant, three publications (Gimeno et al., 2007; Marrugat et al., 2004; Perona et al., 2011) reported on the same study, two of which provided information on LDL‐c particle‐related analyses only (Gimeno et al., 2007; Perona et al., 2011). The Panel considers that these two publications do not provide additional information regarding the claimed effect beyond what is reported in the original publication (Marrugat et al., 2004).

For the reasons outlined above, the Panel considers that no conclusions can be drawn from 5 (Al‐Rewashdeh, 2010; Gimeno et al., 2007; Hernáez et al., 2015; Khandouzi et al., 2021; Perona et al., 2011) of the 11 publications provided by the applicant as being pertinent for the scientific substantiation of the claim. The remaining six studies are discussed later in this section.

In addition to the pertinent studies, the applicant submitted six human intervention studies as being supportive of the claim. Of these, four studies do not allow conclusions to be drawn for the scientific substantiation of the claim because they either:

• reported on the effect of an olive oil with high polyphenol content only (single‐arm, uncontrolled study (Otrante et al., 2021)),
• reported results from the EUROLIVE study stratified by geographical region for the three olive oil intervention arms (i.e. with different polyphenol content) combined (Bondia‐Pons et al., 2007) or
• investigated the effect of olive oils with unknown polyphenol content in the context of other dietary interventions versus low‐fat diets without controlling for the co‐interventions or the fat quality/content of the control diet (the PREDIMED and CORDIOPREV studies, with several publications submitted).

The remaining two studies reported in three publications (Fitó et al., 2005; Fitó et al., 2008; Moreno‐Luna et al., 2012) assessed the effect of olive oil polyphenols per se (i.e. compared the effect of similar amounts of olive oil with different polyphenol content under similar conditions).

The first study (Fitó et al., 2005; Fitó et al., 2008) was a randomised, placebo‐controlled, crossover study in 46 patients on secondary prevention for CHD. Participants consumed 50 mL/day of olive oil with either high (161 mg/kg measured by HPLC, providing approximately 7.4 mg/day of polyphenols) or low (14 mg/kg, providing approximately 0.6 mg/day of polyphenols) polyphenol content. Each intervention phase lasted 3 weeks, separated by a 2‐week washout period during which all participants received the low‐polyphenol olive oil. The declared primary outcomes were plasma concentrations of phenolic compounds and oxidative stress (no sample size calculations were provided). A secondary objective was to assess blood pressure (BP) in hypertensive individuals with stable CHD. The blood lipid profile was also measured. A total of three patients withdrew for reasons unrelated to the intervention and three patients were non‐compliant. Of the 40 patients for whom data were provided, all were on aspirin, 33 were on statins, 20 on ACE‐inhibitors, 26 on beta‐blockers, 11 on long‐acting nitrates and 11 on calcium channel antagonists. The Panel notes that, except for the long‐acting nitrates, aspirin and statins, all other pharmacological therapies are used in the management of hypertension. Changes in BP during the study were only reported for 19 subjects with a diagnosis of hypertension at baseline, and a subgroup analysis was provided according to baseline SBP ≥ 140 mm Hg (n = 9) or < 140 mm Hg (n = 10). The criteria used to establish the diagnosis of hypertension and the selection process for these 19 subjects were not defined. The authors reported a significant decrease in SBP during the high versus the low olive oil polyphenol consumption, which was restricted to patients with SBP ≥ 140 mmHg at baseline on subgroup analysis, and no between‐period differences in DBP. The authors also reported that no period (time) effect, intervention‐period interaction or interaction with medical treatments were observed. Considering that at least 20 patients were on ACE‐inhibitors and that half of the 19 hypertensive subjects had SBP above the therapeutic target, it is unclear how these 19 patients were selected from the sample of 40, whether all patients were on pharmacological treatment for hypertension or not, how they were distributed between the intervention sequences or how the interaction with medical treatments was tested for such a small sample size. Changes in the blood lipid profile were reported for all 40 subjects, 33 of whom were on statins. No changes in blood LDL‐c concentrations were observed. The Panel notes that this study is at high risk of selective reporting and considers that no conclusions can be drawn for the scientific substantiation of the claim.

The second study (Moreno‐Luna et al., 2012) was a randomised, crossover intervention in young women (mean age: 27 years) with high‐normal blood pressure (SBP of 120–139 mm Hg or DBP of 80–89 mmHg) or stage 1 essential hypertension (SBP of 140–159 mmHg DBP of 90–99 mmHg) not on pharmacological treatment for hypertension. The Panel considers that the results obtained in this study group could be extrapolated to the target population for which the claim is intended (EFSA NDA Panel, 2018). Forty women meeting the inclusion criteria were consecutively sampled, of which six refused enrolment. Following a 4‐month run‐in on a standardised Mediterranean‐style diet, participants were randomised and underwent two 2‐month intervention periods (separated by a 4‐week washout) during which they consumed 60 mL/day of olive oil with either a high polyphenol content (total polyphenols 564 mg/kg measured by reverse‐phase HPLC‐DAD, providing approximately 31 mg/day of polyphenols) or no polyphenols. Compliance with the intervention was assessed using daily food records. It is unclear from the publication whether the study was planned as single or double blind (contradictory information in the abstract, materials and methods and discussion). Furthermore, the authors acknowledged that it could have been unblinded owing to the strong taste of the olive oil high in polyphenols.

At the end of each intervention period, BP and endothelial function were measured and blood samples were collected for the indirect determination of plasma nitric oxide (via total nitrites/nitrates) and ox‐LDL concentrations, as well as for asymmetric dimethylarginine (ADMA) and hs‐CRP concentrations in serum. Peripheral (brachial) SBP and DBP were measured in the right arm after 10 minutes in a supine position three times at 2‐minute intervals using an automated oscillometric device. The mean of the three measurements was used for data analysis. It is unclear which was the primary outcome of the study, as sample size calculations were not reported.

Ten women withdrew after the first dietary intervention phase (six due to protocol violations, three due to oil intolerance and one due to relocation), leading to a 29% attrition rate. No information is provided about the characteristics of women dropping out. A total of 24 women completed the study. Statistical analyses were conducted in completers only. Changes after the polyphenol‐rich and polyphenol‐free olive oil diets with respect to the run‐in period (baseline values) were assessed using Student's t‐test for paired samples for normally distributed variables and the Wilcoxon paired rank test when variables were not normally distributed. It is unclear from the publication how differences between intervention periods were assessed (i.e. ANOVA is only mentioned in a footnote to Table B.1), or whether and how carry‐over effects were investigated. The Panel considers that, owing to the important methodological limitations (e.g. high drop‐out rate, statistical analyses in completers only, unclear how data were analysed in relation to comparisons between intervention periods) and poor reporting of the study (contradictory and incomplete information regarding blinding and data analysis), no conclusions can be drawn for the scientific substantiation of the claim.

As part of the evidence submitted for the mechanism by which olive oil polyphenols might reduce BP, the applicant provided a publication reporting on a random subsample (n = 18) of the EUROLIVE study (Martín‐Peláez et al., 2017). This subsample was selected to investigate the effect of olive oil polyphenols on blood pressure‐related gene expression. The Panel notes that, among other parameters, this publication reports on changes in blood pressure within this subsample, an outcome not addressed in the Covas et al. (2006) publication analysing the entire EUROLIVE study population (n = 200). The Panel considers this publication as pertinent to the scientific substantiation of the claim.

The main characteristics and results of the five studies submitted (reported in seven publications) that the Panel considers for the scientific substantiation of the claim are presented in Table B.1, Appendix B. All studies investigated changes in blood LDL‐c concentrations, and four studies investigated changes in BP. Covas et al. (2006) reported blood LDL‐c results for the entire EUROLIVE study population, while Martín‐Peláez et al. (2017) provided BP results for a random subsample of the EUROLIVE study. Sarapis et al. (2020) and Sarapis et al. (2023) reported results for BP and blood LDL‐cholesterol concentrations, respectively, from the same study.

The Panel notes that, with few exceptions (Marrugat et al., 2004; Sanchez‐Rodriguez et al., 2018), these intervention studies report on the content of polyphenols (rather than total phenolic compounds) in the olive oils tested, and therefore, this term will be used for the description of the pertinent studies. The Panel also notes that the terms polyphenols and phenolic compounds are used interchangeably in some studies.

When the daily doses of olive oil polyphenols were not reported in the studies, they were calculated based on the polyphenol content per kilogram of oil and the daily dose of olive oil given in millilitres, assuming an olive oil density of 0.916 g/mL (FAO/WHO, 2024).

Human intervention studies on the effect of olive oil polyphenols on blood LDL‐c concentrations

In a randomised, double‐blind, crossover trial (Fernández‐Castillejo et al., 2016), 33 hypercholesterolaemic individuals not on cholesterol‐lowering medication with a mean age of ~55 years consumed 25 mL/day of either olive oil with low polyphenol content (80 mg/kg oil, 1.8 mg/day) or polyphenol‐enriched olive oil (500 mg/kg oil, 11.5 mg/day) for a 3‐week period, separated by a 2‐week washout interval. The Panel considers that the results of a third intervention arm involving olive oil enriched with both olive oil and thyme polyphenols are not pertinent to the claim under evaluation and will not be discussed further. The primary outcome of the study was the total HDL‐particle number. Plasma LDL‐c concentrations, calculated using the Friedewald equation, were a secondary outcome. The analytical method used to quantify the content of polyphenols in olive oil is not reported in the paper. The Panel notes that another publication (Farràs et al., 2015) reported on the total phenolic content and the phenolic profile of the same olive oils used in this trial as assessed by the Folin–Ciocalteu method and high‐performance liquid chromatography coupled to tandem mass spectrometry (HPLC/MS/MS), respectively. Compliance with the interventions was confirmed via measurement of 24‐hour urinary hydroxytyrosol sulfate using HPLC‐ESI‐MS/MS.

Between group differences in blood LDL‐c concentrations and SBP changes during the study were assessed by analysis of covariance (ANCOVA) with the following covariates: age, gender, sequence of olive oil administration, baseline LDL‐c concentrations and baseline SBP values. Consumption of polyphenol‐enriched olive oil significantly reduced LDL‐c concentrations compared to olive oil with low polyphenol content (mean change: −13 mg/dL [95% CI: −17, −9.40] vs. +1 mg/dL [95% CI: −3.2, 5.2], respectively). The between‐group difference in LDL‐c reduction was statistically significant (−14 mg/dL [95% CI: −20, −8.6]; p < 0.05).

Four RCT crossover studies assessed the effect of olive oils with high and low polyphenol content on blood LDL‐c concentrations in healthy individuals. Three RCTs (Covas et al., 2006; Sanchez‐Rodriguez et al., 2018; Sarapis et al., 2023), all with a duration of the intervention of 3 weeks and washout periods of 2 weeks, with sample sizes ranging from 50 to 200 individuals, did not show a significant decrease in LDL‐c concentrations when comparing the high and low olive oil polyphenol interventions. Daily intake of polyphenols from olive oil ranged from 13.2 to 17.6 mg in the high polyphenol intervention and from 0.1 to 4.6 mg in the low polyphenol intervention. The fourth study did not test between‐group differences in blood LDL‐c concentrations (Marrugat et al., 2004).

The Panel notes that one RCT in 33 hypercholesteraemic individuals showed a beneficial effect of olive oil polyphenols on blood LDL‐c concentrations when consumed at doses of 11.5 mg/day for 3 weeks (Fernández‐Castillejo et al., 2016), whereas no effect was observed in RCTs conducted in healthy individuals with larger sample sizes of up to 200 participants and daily olive oil polyphenol doses up to 17.6 mg (Covas et al., 2006; Sanchez‐Rodriguez et al., 2018; Sarapis et al., 2023). The Panel also notes that evidence on the sustainability of any potential effect on blood LDL‐c with continuous consumption of olive oil polyphenols over longer periods of time (e.g. ≥ 8 weeks) has not been provided (see Section 3.2).

Human intervention studies on the effect of olive oil polyphenols on blood pressure

Four of the crossover RCTs discussed above in relation to blood LDL‐c concentrations also assessed changes in BP (Fernández‐Castillejo et al., 2016; Martín‐Peláez et al., 2017;Sanchez‐Rodriguez et al., 2018; Sarapis et al., 2020). Participants with hypertension were excluded at recruitment in all the studies and BP was not the primary outcome in any of them. Peripheral (brachial) BP was measured with a mercury sphygmomanometer after at least a ten‐minute rest in the seated position once (Fernández‐Castillejo et al., 2016) or twice (average of two measurements (Martín‐Peláez et al., 2017; Sanchez‐Rodriguez et al., 2018)), except in one study (Sarapis et al., 2020) which measured both peripheral and central BP using a SphygmoCor XCEL device (mean of the last two out of three measurements) following a 5‐minute rest in the supine position. Pulse pressure (PP) was calculated as the difference between SBP and DBP in two studies (Sanchez‐Rodriguez et al., 2018; Sarapis et al., 2020). Sample size ranged from 18 to 58 individuals and the daily amount of olive oil polyphenols from 0.1 to 4.7 mg in the low polyphenol period and from 8.4 to 17.6 mg in the high polyphenol period. No significant differences between intervention periods were observed in any BP measurement in any of the studies considered, except for the study by Martín‐Peláez et al. (2017).

In the randomised, double‐blind, crossover trial conducted as a random subsample of the EUROLIVE study (Martín‐Peláez et al., 2017), 18 participants received 25 mL/day of olive oil with either high (366 mg/kg of oil) or low (2.7 mg/kg of oil) phenolic content (resulting in daily polyphenol intake of 8.4 and 0.1 mg/day respectively) for 3 weeks, and with a 2‐week washout period in between the two interventions. Although the EUROLIVE study also included a third intervention period with olive oil containing medium phenolic content (164 mg/kg of oil, 3.8 mg/day), BP data for this intervention period were not reported in the publication. The primary outcome was the change in the expression of BP‐related genes in peripheral blood mononuclear cells.

Relative to baseline, the between‐group differences for mean changes (± SEM) in SBP (−4.22 ± 1.81 mmHg and + 0.44 ± 1.81 mmHg during the high and low olive oil polyphenol interventions, respectively), assessed using adjusted general linear mixed models, were not statistically significant (p = 0.06). Mean change in DBP from baseline was statistically significantly different between the low and high olive oil polyphenol interventions (2.94 ± 1.34 mmHg vs. −2.11 ± 1.34 mmHg, respectively; p = 0.007). The Panel notes the small sample size of this study.

The Panel considers that the four crossover RCTs described above, which were all conducted in healthy, normotensive individuals, do not show an effect of olive oil polyphenols on SBP. The Panel also considers that some of these studies, with a sample size between 18 and 58 individuals, may have been underpowered to assess between‐group differences in BP changes, which were not the primary outcome in any of the studies.

Mechanism of action

LDL‐cholesterol

The applicant suggested that phenolic compounds in olive oil could reduce LDL‐c concentrations by reducing systemic oxidative stress, which correlates with small and dense LDL particles prone to oxidation, by increasing lipoprotein lipase (LPL) activity and by up‐regulating cholesterol efflux.

In support of the mechanism of action, the applicant provided a cross‐sectional study reporting on the association between diacron reactive oxygen metabolites (d‐ROMs) and small and dense LDL particles (Kotani et al., 2012), a narrative review on the role of LPL on lipoprotein metabolism (Otarod & Goldberg, 2004), a rat study on the relationship between the antioxidant capacity of plasma and LPL activity and lipoprotein metabolism following interventions with lipoic acid and N‐acetylcysteine (Yang et al., 2006), a narrative review on the mechanisms by which dietary polyphenols in general could decrease blood LDL‐c concentrations in humans (Sun et al., 2021) and a single dose, 5‐h human intervention with olive oil polyphenols on gene expression in which cholesterol efflux was not measured (Farràs et al., 2013).

The Panel notes that, although olive oil polyphenols have been shown to decrease oxidative damage to LDL‐c particles in a dose–response manner, this effect did not translate into changes in blood LDL‐c concentrations (Covas et al., 2006). The Panel also notes that no evidence has been provided for an effect of phenolic compounds on LPL activity or on cholesterol efflux.

The Panel considers that no evidence has been provided for a plausible mechanism by which phenolic compounds in olive oil could reduce blood LDL‐c in humans.

Blood pressure

The applicant suggests that phenolic compounds in olive oil could reduce BP by inducing endothelium‐dependent vasodilation through the increased availability of nitric oxide metabolites (serum nitrites/nitrates, NOx) and endothelium‐derived hyperpolarising factor (EDHF) in blood vessels.

The applicant provided two crossover RCTs which investigated the effect of olive oil polyphenols on blood NOx concentrations and on endothelium‐dependent vasodilation using the ischaemic reactive hyperaemia (IRH) technique. In the first study (Ruano et al., 2005), 21 hypercholesterolaemic adults consumed breakfasts with 40 mL of olive oil, either high (400 mg/kg of oil, i.e. 14.7 mg) or low (80 mg/kg of oil, i.e. 2.9 mg) phenolic content. NOx was measured at 0, 30, 60, 120 and 240 min after consumption, and IRH at baseline and at 120 and 240 min after each meal. Both NOx and endothelium‐dependent vasodilation were significantly higher after the olive oil with the high versus the low polyphenol content in the 4 h after consumption of the meals. In a longer term study already described at the beginning of this section (Moreno‐Luna et al., 2012), a significant increase in NOx and endothelium‐dependent vasodilation was also reported in women with high‐normal BP or stage 1 untreated hypertension (n = 24) after a period of 2 months consuming olive oil high in polyphenols (providing 31 mg/day of polyphenols), as compared to the 2‐month period in which they consumed an olive oil without polyphenols. SBP and DBP were reported to decrease accordingly during the high polyphenol period in these women. The Panel considers that, although no conclusions could be drawn from this small study for the scientific substantiation of an effect of olive oil polyphenols on BP owing to significant methodological limitations and poor reporting, it provides, together with the single meal study by Ruano et al. (2005), some evidence for a mechanism by which these compounds could mediate a reduction in BP.

In addition, the applicant also suggested that olive oil polyphenols may be involved in the expression of genes that play a role in the modulation of the renin–angiotensin–aldosterone system (RAAS). This hypothesis was tested in the study by Martín‐Peláez et al. (2017) described above in relation to BP. Olive oil polyphenols tended to decrease the expression of some genes involved in the modulation of the RAAS system in peripheral blood mononuclear cells, but differences between the high and low olive oil polyphenol interventions were not statistically significant, possibly owing to the small sample size of the study (n = 18).

The Panel notes that other references submitted by the applicant are less relevant to this application. Two narrative reviews (Andriantsitohaina et al., 2012; Stoclet et al., 2004) provided in support of the proposed mechanisms address dietary polyphenols in general rather than olive oil polyphenols specifically. The applicant also cited several studies investigating the effects of olive leaf polyphenols, primarily oleuropein, on BP (de Bock et al., 2013; Perrinjaquet‐Moccetti et al., 2008; Rahimianfar, 2022). The Panel notes that the phenolic profile of olive leaf extracts differs from that of olive oils, with oleuropein being considerably more abundant in olive leaves, and that while these studies hypothesise mechanisms of action consistent with those suggested by the applicant, none of them provide direct experimental evidence validating these pathways.

The Panel considers that, whereas the applicant has provided some evidence that phenolic compounds in olive oil could increase NOx, endothelial‐mediated vasodilation, and possibly the expression of genes involved in the modulation of the RAAS, which are all well‐known mechanisms involved in the regulation of BP in humans, no evidence has been provided that these changes are consistently achieved upon consumption of olive oil phenolic compounds, or that the magnitude and/or duration of these changes effectively translate into a reduction of BP in vivo in humans.

Weight of evidence

In weighing the evidence with regard to LDL‐c, the Panel took into account that, although one human intervention study in hypercholesterolaemic individuals showed a reduction in blood LDL‐c following daily consumption of olive oil polyphenols for 3 weeks (Fernández‐Castillejo et al., 2016), these results are not supported by other studies (Covas et al., 2006; Sanchez‐Rodriguez et al., 2018; Sarapis et al., 2023) and have not been replicated in other population groups or settings. The Panel also took into account that no evidence was available for the sustainability of the effect with continuous consumption of olive oil polyphenols over longer periods of time (e.g. ≥ 8 weeks), and that no evidence for a plausible mechanism by which olive oil phenolic compounds could exert the claimed effect was provided.

In weighing the evidence with regard to SBP, the Panel took into account that, although some evidence for a plausible mechanism by which phenolic compounds could exert the claimed effect has been provided, the studies submitted for the scientific substantiation of the claimed effect did not show an effect of olive oil polyphenols on SBP (Fernández‐Castillejo et al., 2016; Martín‐Peláez et al., 2017; Sanchez‐Rodriguez et al., 2018; Sarapis et al., 2020).

The Panel concludes that a cause‐and‐effect relationship has not been established between the consumption of phenolic compounds in olive oil and the reduction of blood LDL‐c or SBP.

CONCLUSIONS

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On the basis of the data presented, the Panel concludes that:

• The food/constituent, phenolic compounds naturally present in olive oil, which is the subject of the health claim, is sufficiently characterised.
• The claimed effect proposed by the applicant is lowering of LDL‐cholesterol and systolic blood pressure. The target population proposed by the applicant is ‘the general healthy and subgroup with mildly raised LDL‐c and blood pressure’. The Panel considers that lowering of LDL‐cholesterol and systolic blood pressure are beneficial effects by reducing the risk of coronary heart disease.
• A cause‐and‐effect relationship has not been established between the consumption of phenolic compounds naturally present in olive oil and the reduction of blood LDL‐c or SBP.

DOCUMENTATION AS PROVIDED TO EFSA

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Health claim application pursuant to Article 14 of Regulation (EC) No 1924/2006 (EFSA‐Q‐2024‐00470, HC‐2024‐22631). Submitted by QvExtra! Internacional.

STEPS TAKEN BY EFSA

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1. The application was received by EFSA on 16/07/2024. The application was validated on 09/10/2024, and the scientific evaluation started.
2. EFSA sent a first Additional Data Request (ADR) letter to the Applicant on 21/10/2024. The clock was stopped and restarted on 19/11/2024.
3. The application on was open for public consultation from 21/02/2025 to 14/03/2025 (PC‐1329).
4. During its meeting on 06/05/2025, the NDA Panel, having evaluated the data, adopted an opinion on the scientific substantiation of a health claim related to “Phenolic compounds naturally present in olive oil and lowering of blood LDL‐cholesterol and systolic blood pressure, therefore reducing the risk of coronary heart disease: evaluation of a health claim pursuant to Article 14 of Regulation (EC) No 1924/2006”.

REQUESTOR

Competent Authority of Spain following an application by QvExtra! Internacional.

QUESTION NUMBER

EFSA‐Q‐2024‐00470

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PANEL MEMBERS

Dominique Turck, Torsten Bohn, Montaña Cámara, Jacqueline Castenmiller, Stefaan De Henauw, Karen Ildico Hirsch‐Ernst, Angeles Jos, Alexandre Maciuk, Inge Mangelsdorf, Breige McNulty, Androniki Naska, Kristina Pentieva, Alfonso Siani and Frank Thies.